The Value of the Serum Vitamin B12 Level in Diagnosing B12 Deficiency

Serum vitamin B₁₂ levels of 2523 individuals were measured using the hemoglobin-coated charcoal assay. In onehospital, the test was performed on 1698patients under hematologic evaluation forerythrocytic abnormalities of all types,while 825 patients from five other hospitals were studied because of suspectedB₁₂ deficiency. The incidence of low serumvitamin B₁₂ was surprisingly low for bothgroups (2.3% and 3.5%, respectively).The value of the test as a diagnostic toolwas further reduced by two characteristicsof physician performance. First, with thosepatients who demonstrated a clear-cutmacrocytic anemia and were suspects forintrinsic factor deficiency (perniciousanemia), extensive evaluations for B₁₂malabsorption were usually carried outprior to the receipt of the low B₁₂ level.Second, when a deficiency state was notsuspected, the return of a low value didnot reliably stimulate physicians to beginevaluation or institute therapy. This wastrue despite the presence of clinical evidence of a possible gastrointestinal abnormality in many of the patients.

Submitted on July 3, 1973 Revised on November 29, 1973 Accepted on November 30, 1973     

Methylmalonic Acid Excretion and Serum Vitamin B12

Urinary methylmalonic acid excretion in 12 healthy persons ranged between 0.6 and 4.7 mg per 24 hours; in 10 patients with serum vitamin B₁₂ at or above 70 pg/ml, less than 5 mg of methylmalonic acid was excreted per 24 hours. In a group of 21 patients with serum vitamin B₁₂ below 70 pg/ml, 18 excreted more than 7 mg per 24 hours (7.8–660 mg).     

Serum Vitamin B12 Concentration after Proximal Gastric Vagotomy

The serum concentration of vitamin B₁₂, blood hemoglobin, and gastric acid secretion capacity was studied preoperatively and 1 and 5 years after proximal gastric vagotomy (PGV) in 15 patients. There was a significant reduction in the mean concentration of vitamin B₁₂ at 1 year, but this disappeared within 5 years after PGV. The serum concentration of vitamin B₁₂, however, remained at all times within the health-related reference interval. The blood hemoglobin concentration was unaltered during the follow-up period. The decrease in gastric acid secretion capacity gained by PGV was permanent, and no tendency to increased acidity was observed during the 5-year period. The temporary decrease in serum concentration of vitamin B₁₂ reflects a PGV-induced diminished production of intrinsic factor in the parietal cells. In the characterization of parietal cell function the determination of serum vitamin B₁₂ concentration is, however, much less sensitive than gastric acid secretion tests. The observed change in vitamin B₁₂ concentration after PGV was subclinical, self-corrected, and thus required no treatment.     

Primary Position Upbeat Nystagmus with Low Serum Vitamin B12

A 38-year-old man presented with primary position upbeat nystagmus accompanied by peripheral neuropathy. The serum vitamin B12 level was low along with high plasma homocysteine level, indicating vitamin B12 deficiency. Cyanocobalamin supplementation showed partial clinical and electrophysiological improvement. Although brain magnetic resonance imaging did not show any abnormal intensity lesions, the electrophysiological findings suggested that a pontomedullary medial lesion was responsible for the upbeat nystagmus. To our knowledge, this is the first case of upbeat nystagmus with low serum vitamin B12. Physicians need to recognize the possibility of vitamin B12 deficiency as a cause of upbeat nystagmus.     

Vitamin B12-binding Protein of Leukocytes as a Possible Major Source of the Third Vitamin B12-binding Protein of Serum

Much evidence suggests that granulocytes are a major source of serumvitamin B₁₂-binding protein (BBP). Thelatter has three components: -1-globulin BBP (Transcobalamin I, TC I),-globulin BBP (TC II), and a recentlydescribed third BBP. Granulocytic BBPhas appeared to be identical to TC Iexcept in electrophoretic mobility. Inthe present study, the dominant BBPof leukocyte extracts from subjectswith and without myeloproliferativedisease behaved like the third serumBBP. With a few exceptions, morethan half the leukocytic binder elutedwith the " globulins" on rapid DEAE-cellulose chromatography. At pH 8.6,electrophoretic mobility of the leukocytic BBP was always ₂ or . At ph4.5, normal and chronic myelogenousleukemia leukocytic BBP, unlike TC Iand TC II, showed little electrophoretic migration. These findings suggestthat leukocytic BBP is probably heterogenous and that its major componentresembles the third serum BBP morethan it does TC I. The third serumBBP, levels of which are elevated insome states of leukocytic proliferation,may derive directly from maturegranulocytes. TC I may arise by addition of sialic acid to the third (granulocytic) BBP under certain circumstances or be released from othercells, such as less mature granulocytes. Much of the confusion in theliterature regarding source and significance of serum BBP may relate toseparating it into only two fractions( globulin and " globulin," or "TC I"and TC II) instead of into three fractions.

Submitted on March 2, 1972 Accepted on April 26, 1972     

Serum Lysozyme and Vitamin B12 Binding Capacity in Myeloproliferative Disorders

Summary Estimations of serum lysozyme (muramidase), total B₁₂ binding capacity (TB₁₂BC) and folate were performed in 122 patients: 69 with myeloproliferative disorders (39, polycythaemia rubra vera (PRV); 10, chronic granulocytic leukaemia, Ph¹-chromosome positive (CGL); 20, myelosclerosis) and 53 with other disease which affect leucocyte production or turnover (17, monocytic leukaemias; 20, megaloblastic anaemia; 15, neutropenia; and a single case of red cell aplasia progressing to a myeloproliferative disorder). The highest serum lysozyme levels were found in monocytic leukaemia. Serum lysozyme concentrations were also elevated in myelosclerosis and to a lesser extent in CGL and in PRV. High levels in PRV occurred in patients developing myelosclerosis or with active disease, resistant to treatment. Significantly higher concentrations of lysozyme were present in patients with myelosclerosis following PRV than in patients with the primary form of the disease. Patients with myeloproliferative diseases and high lysozyme concentrations tended to have low serum folate levels. Slightly raised levels were found in about 50% of patients with megaloblastic anaemia. Moderately high serum lysozyme concentrations also occurred in patients with neutropenia and hypercellular bone marrows but not in those with hypocellular marrows. TB₁₂BC concentrationswere increased in the myeloproliferative disorders, especially in CGL and to a lesser extent in myelosclerosis and least of all in PRV. The results suggest that serum lysozyme reflects granulocyte turnover (except in monocytic leukaemia) while TB₁₂BC (providing liver function is normal) correlates closely with the total blood (and possibly marrow and splenic) granulocyte pool. The ratio between serum lysozyme and TB₁₂BC proved to be a useful index of the balance between granulocyte turnover and total granulocyte pool in individual patients.     

Influence of Age and Stomach Function on Serum Vitamin B12 Concentration

Serum vitamin B₁₂ (B₁₂), maximal gastric acid output (MAO), and B₁₂ absorption were determined in 82 subjects, age 32 to 85 years, who had normal absorption of radiocyanocobalamin. In 46 of the patients the gastric intrinsic factor (IF) was also measured. Serum B₁₂ concentration and MAO varied widely in all age groups from abnormally low to definitely normal. The mean values for serum B₁₂ and MAO, however, declined very similarly with advancing age owing to an increased incidence of low values for these two measurements in the aged. There was no significant fall in the mean B₁₂ absorption or IF secretion as a function of old age. Achlorhydric and hypochlorhydric patients invariably had lower mean serum B₁₂ concentrations than those with adequate MAO. Conversely, patients with normal MAO all had normal serum B₁₂ levels. Serum B₁₂ concentration, although correlating with both MAO and IF secretion, showed a closer relationship to the former than to the latter. These findings suggest that the stomach, aside from producing the IF, plays an important role in maintaining a normal serum B₁₂ concentration.     

Use of Serum Vitamin B12 Level as a Marker to Differentiate Idiopathic Noncirrhotic Intrahepatic Portal Hypertension from Cryptogenic Cirrhosis

Background and Aims

Idiopathic non-cirrhotic intrahepatic portal hypertension (NCIPH) is often mis-diagnosed as cryptogenic cirrhosis. Serum vitamin B12 levels can be raised in cirrhosis, probably because of excess release or reduced clearance. Because NCIPH is characterised by long periods of preserved liver function, we examined whether serum B12 level could be used as a marker to differentiate NCIPH from cryptogenic cirrhosis.

Methods

We analysed serum B12 levels in 45 NCIPH and 43 cryptogenic cirrhosis patients from January 2009 to September 2011.

Results

Serum B12 levels were significantly lower in NCIPH patients than in cryptogenic cirrhosis patients (p < 0.001) and were useful in differentiating the two disorders (area under ROC: 0.84; 95 % C.I: 0.76–0.93). Low serum B12 level (≤250 pg/ml) was noted in 25/72 (35 %) healthy controls, 14/42 (33 %) NCIPH patients, and 1/38 (3 %) cryptogenic cirrhosis patients. In patients with intrahepatic portal hypertension of unknown cause, serum B12 level ≤ 250 pg/ml was useful for diagnosing NCIPH (positive predictive value: 93 %, positive likelihood ratio 12.7), and serum B12 level >1,000 pg/ml was useful in ruling out NCIPH (negative predictive value: 86 %, negative likelihood ratio: 6.67). Low serum B12 levels (≤250 pg/ml) correlated with diagnosis of NCIPH after adjusting for possible confounders (O.R: 13.6; 95 % C.I:1.5–126.2). Among patients in Child’s class A, serum B12 level was ≤250 pg/ml in 14/35 NCIPH patients compared with 1/21 cryptogenic cirrhosis patients (O.R: 13.3; 95 % C.I: 1.6–111).

Conclusion

Serum vitamin B12 level seems to be a useful non-invasive marker for differentiation of NCIPH from cryptogenic cirrhosis.     

The Plasma Disappearance of Radioactive Vitamin B12 in Myeloproliferative Diseases and Other Blood Disorders

1. The plasma disappearance of a small intravenous dose of radioactivevitamin B₁₂ was determined in control subjects and in patients with variousblood disorders.

2. A delayed, sometimes irregular, disappearance was observed in themajority of patients with acute and chronic myelogenous leukemia, myeloidmetaplasia, and polycythemia vera.

3. Disappearance was normal in the lymphogenous leukemias, secondarypolycythemia and relative polycythemia.

4. The abnormalities observed are believed to indicate an abnormality ofvitamin B₁₂ metabolism common to the diseases of the myeloproliferativegroup and are further evidence of the close relationship between thesediseases.

Submitted on July 3, 1961 Accepted on September 15, 1961     

Vitamin B12 Metabolism in Myelomatosis

In 38 patients with myelomatosis the serum cobalamin varied from 34 pmol/l to 404 pmol/l, median 181.5 pmol/l, which is significantly lower than the levels in 22 control persons with range 173–535 pmol/l, median 265 pmol/l. In spite of low serum cobalamin no symptoms of vitamin B₁₂ deficiency could be demonstrated in any of the patients, except for the one patient who had a serum cobalamin of 34 pmol/l. Mean values for Hb, MCV, PCV, serum lactate-dehydrogenase, adjusted red cell folate and nucleated neutrophil count were similar in a group of patients with a serum cobalamin below 160 pmol/l and a group of patients with higher serum cobalamin values. The decrease in serum cobalamin is due in part to a reduction in the major cobalamin binder (TC-I) in serum. Measuring serum cobalamin in relationship to gastric acid secretion, we found a significantly higher frequency of hypo- and achlorhydria in patients with serum cobalamin below 160 pmol/l although the intestinal absorption of vitamin B₁₂ was normal by a Schilling test. Although our finding of low saturation of TC-I in serum seems to demonstrate decreased vitamin B₁₂ content in the body in myelomatosis, the lack of evidence for a functional vitamin B₁₂ deficiency speaks against giving a supplement to patients with myelomatosis.     

血清β2微球蛋白测定在某些血液病及淋巴瘤中的临床意义

本文对３２８例血液病患者的血清β微球蛋白进行了检测，发现在恶性血液后，巨幼细胞性贫血和溶血性贫血患者中血清β２Ｍ水平明显高于正常（Ｐ均〈０．０５），而在其它良性血液病中，血清β２Ｍ水平与正常人比较差异无明显性（Ｐ〉０．０５），动态观察了３０例非霍奇金淋巴瘤，缓解前后血清β２Ｍ水平差异有显著性。     

Serum Vitamin B12 and Erythrocyte Folate in Chronic Uraemia and after Renal Transplantation

Serum B₁₂ and erythrocyte folate were measured in 16 non-dialysed uraemic patients, 28 peritoneal dialysed patients, 28 haemodialysed patients, 14 renal transplanted patients with normal renal function and 49 healthy control subjects. Serum B₁₂ values in non-dialysed uraemic patients were higher than in control subjects (P < 0.001), peritoneal dialysed (P < 0.05), and transplanted patients (P < 0.01). Serum B₁₂ values in peritoneal dialysed, haemodialysed and transplanted patients were not significantly different from the control group. Erythrocyte folate values in non-dialysed uraemic patients were lower than in controls (P < 0.03), but all subjects had values within the normal range. Erythrocyte folate values in peritoneal dialysed, haemodialysed and renal transplanted patients were not significantly different from the control group, although 2 peritoneal and 6 haemodialysed patients had subnormal values. Blood and bone marrow examination, performed in 64 patients, demonstrated no megaloblastic changes.     

An Improved Radioisotope Dilution Assay for Serum Vitamin B12 Using Hemoglobin-coated Charcoal

A radioisotope dilution assay for vitamin B₁₂, using hemoglobin-coatedcharcoal, was modified in several respects, the most prominent of whichwas the use of cyanide extraction ofsera. With these modifications, the B₁₂levels were significantly higher in serafrom normal subjects and patients withfolate deficiency, whereas sera frompatients with pernicious anemia andother B₁₂-deficient states were onlyminimally affected. The use of cyanideextraction thus resulted in a clearerdifferentiation of B₁₂-deficient serafrom other sera; all 23 patients withpernicious anemia had B₁₂ levels below 140 pg/ml, whereas all of 85 normal and 218 folate-deficient subjectshad B₁₂ levels above 156 pg/ml. Themicrobiologic assay with Euglenagracilis was similarly affected by cyanide extraction of sera. Thus, it appears that the use of cyanide resultsin more complete extraction of B₁₂from serum proteins.

Submitted on June 28, 1971 Revised on September 21, 1971 Accepted on September 23, 1971     

Vitamin B12 and vitamin B12 binding proteins in liver diseases

Serum vitamin B12 and vitamin B12 binding proteins (transcobalamins, TCS) were determined in patients with malaria, amoebic liver abscess, carcinoma of the liver, infectious hepatitis, cirrhosis and chronic myelocytic leukemia (CML) as well as in 60 blood donor subjects. Serum vitamin B12 in patients with infectious hepatitis, cirrhosis and CML were higher than that of the normal subjects. The values of unsaturated vitamin B12 binding capacity (UBBC) in patients with carcinoma of the liver, infectious hepatitis, cirrhosis were lower while that of patients with CML were higher than that of the normal subjects. A markedly increased TCI and decreased TCII was observed in patients with CML while these changes was much less in patients with other liver diseases. The difference was possibly due to a flooding of vitamin B12 from damaged liver cells into the circulation and the decreased synthesis of transcobalamins in patients with liver diseases while the increased granulocytes, the source of TCI, was much increased in patients with CML.